Amyloid β-peptide 31-35-induced neuronal apoptosis is mediated by caspase-dependent pathways via cAMP-dependent protein kinase A activation

This study aims to investigate the roles of the protein kinase A (PKA)- and caspase-dependent pathways in amyloid β-peptide 31-35 (Aβ[31-35])-induced apoptosis, and the mechanisms of neuroprotection by group III metabotropic glutamate receptor (mGluR) activation against apoptosis induced by Aβ[31-35]in cortical neurons. We demonstrated that Aβ[31-35]induces neuronal apoptosis as well as a significant increase in caspase-3, -8 and -9. Activation of group III mGluRs by L-serine-O-phosphate and (R, S)-4-phosphonophenylglycine (two group III mGluR agonists), which attenuate the effects of Aβ[31-35], provides neuroprotection to the cortical neurons subjected to Aβ[31-35]. We also showed that Rp-cAMP, an inhibitor of cAMP-dependent PKA, has the ability to protect neurons from Aβ[31-35]-induced apoptosis and to reverse almost completely the effects of Aβ[31-35]on the activities of caspase-3. Further, we found that Sp-cAMP, an activator of cAMP-dependent PKA, can significantly abolish the L-serine-O-phosphate- and (R, S)-4-phosphonophenylglycine-induced neuroprotection against apoptosis, and decrease caspase-3, -8 and -9 in the Aβ[31-35]-treated neurons. Our findings suggest that neuronal apoptosis induced by Aβ[31-35]is mediated by the PKA-dependent pathway as well as the caspase-dependent intrinsic and extrinsic apoptotic pathways. Activation of group III mGluRs protects neurons from Aβ[31-35]-induced apoptosis by blocking the caspase-dependent pathways. Inhibition of the PKA-dependent pathway might also protect neurons from Aβ[31-35]-induced apoptosis by blocking the caspase-dependent pathways. Taken together, our observations suggest that Aβ[31-35]might have the ability to activate PKA, which in turn activates the caspase-dependent intrinsic and extrinsic apoptotic pathways, inducing apoptosis in the cortical neurons. © 2007 The Authors Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2007.